Alzheimer's disease (AD) is a devastating, progressive dementia with no known prevention or cure. A prevailing (though controversial) hypothesis of AD progression postulates that the disease process is instigated and sustained by over-production and secretion of ?-amyloid (A?) polypeptides. Unfortunately, all efforts to-date to reverse or arrest disease progression by reducing or blocking A? deposits have failed, possibly because they were applied too late in the process, when irreversible damage has already occurred and when disease progression may no longer be A?-dependent. A consistent finding both in humans and in mouse models at earlier stages of the disease is specific loss of somatostatin-containing (SOM) inhibitory interneurons and synapses in the cerebral cortex. Our central hypothesis, based on published research and our preliminary data, is that normal functioning of SOM interneurons and synapses is disrupted very early in the progression of the disease, well before these neurons actually die and before any of the histological or behavioral manifestations of the disease are evident. Furthermore, this dysfunction may play a facilitator or even obligatory role in AD progression. The goal of the current pilot project, is to validate and characterize early disruption to SOM interneuron function and structure in a preclinical AD model, thereby establishing a model system for elucidating the cellular and molecular mechanisms underlying SOM interneuron vulnerability in AD. Understanding these mechanisms may help identify early disease biomarkers which would enable pre-clinical and clinical trials of early therapeutic interventions. It may also reveal obligatory cellular or biochemical nodes in the early stages of disease progression, which could be targeted by novel interventions attempting to slow down the disease process or even nip it in the bud.